This invention relates to pharmaceutical preparations. In particular, this invention relates to pharmaceutical preparations containing alendronate sodium.
Alendronate sodium is a white, crystalline, non-hygroscopic powder. It is soluble in water, very slightly soluble in alcohol, and practically insoluble in chloroform. Typically, alendronate sodium Tablets for oral administration contain either 6.53, 13.05 mg or 52.21 mg of alendronate monosodium salt trihydrate, which is the molar equivalent of 5.0, 10.0 mg and 40.0 mg, respectively, of free acid, and the typically, the following inactive ingredients: microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, and magnesium stearate.
Alendronate sodium belongs to a class of chemical compounds known as Bisphosphonates, which are synthetic analogs of pyrophosphate that binds to bone hydroxyapatite. Alendronate sodium is chemically described as (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate. The empirical formula of alendronate sodium is C4H12NNaO7P2.3H2O and its formula weight is 325.12. Alendronate sodium is therefore an aminobisphosphonate that acts on osteoclasts, the bone-resorbing cells. Alendronate inhibits bone resorption with no direct effect on bone formation, although the latter process is ultimately reduced because bone resorption and formation are coupled during bone turnover. Alendronate sodium thus reduces the elevated rate of bone turnover observed in postmenopausal women to the levels found in premenopausal women. As a specific inhibitor of osteoclast-mediated bone resorption. Overall therefore alendronate Sodium reduces the amount of calcium lost from bones and increases the density of bones.
Normally bones are being rebuilt all the time. First, old bone is removed (resorbed). Then a similar amount of new bone is formed. This balanced process keeps the skeleton healthy and strong.
Osteoporosis is a condition that strikes postmenopausal women as a result of estrogen withdrawal and the consequential depletion of calcium via the kidneys, which is hitherto retained by the mechanism of estrogen and the phosphorus calcium ion exchange mechanism. Osteoporosis causes a thinning and weakening of the bones. It is common in women after menopause. Menopause happens when the ovaries stop producing the female hormone, estrogen, or is removed (which may occur, for example, at the time of a hysterectomy). After menopause, bone is removed faster than it is formed, so bone loss occurs and bones become weaker. Therefore, maintaining bone mass is important to keep bones healthy.
In Postmenopausal Women, therefore osteoporosis is characterized by low bone mass that leads to an increased risk of fracture. The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis, indicative of vertebral fracture. Osteoporosis occurs in both males and females but is most common among women following the menopause, when bone turnover increases and the rate of bone resoprtion exceeds that of bone formation. These changes result in progressive bone loss and lead to osteoporosis in a significant proportion of women over age 50. Fractures, usually of the spine, hip, and wrist, are the common consequences. From age 50 to age 90, the risk of hip fracture in women increases 50-fold and the risk of vertebral fracture 15- to 30-fold. It is estimated that approximately 40% of 50-year-old women will sustain one or more osteoporosis-related fractures of the spine, hip, or wrist during their remaining lifetimes. Hip fractures, in particular, are associated with substantial morbidity, disability, and mortality.
Paget""s Disease is a chronic, focal skeletal disorder characterized by greatly increased and disorderly bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.
Clinical manifestations of Paget""s disease range from no symptoms to severe morbidity due to bone pain, bone deformity, pathological fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy.
Alendronate sodium is a suggested treatment in osteoporosis and Paget""s disease Alendronate sodium decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation. In clinical trials, alendronate sodium 40 mg once daily for six months produced highly significant decreases in serum alkaline phosphotase as well as in urinary markers of bone collagen degradation. As a result of the inhibition of bone resorption, alendronate sodium induced generally mild, transient, decreases in serum calcium phosphate. The reduction in serum phosphate may reflect not only the positive bone mineral balance due to alendronate sodium but also a decrease in renal phosphate reabsorption.
Alendronate sodium specifically inhibits Osteoclast-mediated bone resorption thereby preventing resorption. Its mode of action is suggested as follows: At the cellular level, alendronate shows preferential localization to bone resorption sites, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclastic recruitment or attachment, but it does inhibit osteoclast activity. Bones examined 6 and 49 days after alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover. In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.
For the treatment of osteoporosis, the recommended daily dose is 10 mg. For the prevention of osteoporosis the recommended dose is 5 mg daily. And for the treatment of Paget""s disease the dose recommended is 40 mg daily for 6 months.
The Pharmacokinetics of alendronate sodium is as follows:
Relative to an intravenous (IV) reference dose, the mean oral bioavailability in women was 0.7% for conventionally available doses ranging from 5 to 40 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10 mg tablet in men (0.59%) was similar to that in women (0.78%) when administered after an overnight fast and 2 hours before breakfast.
Bioavailability is decreased (by approximately 40%) when 10 mg alendronate was administered either 0.5 or 1 hour before a standardized breakfast, when compared to dosing 2 hours before eating. In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast.
Bioavailability is negligible whether alendronate is administered with or up to two hours after a standardized breakfast. Simultaneous administration of alendronate with coffee or orange juice reduces bioavailability by approximately 60%.
Alendronate transiently distributes to soft tissues following 1 mg/kg IV administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28:1 in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 mg/ml) for analytical detection. Protein binding in human plasma is approximately 78%.
Daily oral doses of alendronate sodium 5, 20, and 40 mg for six weeks) in postmenopausal women produce biochemical changes indicative of dose-dependent inhibition of bone resorption, including decreases in urinary calcium and urinary markers of bone collagen degradation (such as deoxypyridinoline and cross-linked N-telopeptides of type 1 collagen). These biochemical changes tended to return toward baseline values as early as 3 weeks following the discontinuation of therapy.
In the existing mode of delivery, a particular limitation with the delivery of this drug is that there is fear of the drug sticking and causing deterioration to the gastrooesophagal mucous linings of the esophagus with the possibility of ulceration and bleeding. Esophageal adverse experiences, such as esophagitis, esophageal ulcers and erosions have been reported presented with dysphagia, odynophagia or retrostemal pain.
The risk of severe oesophageal adverse experiences appears to be greater in patients who lie down after taking alendronate sodium and/or who fail to swallow it with a full glass of water. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient because of possible irritant effects on the upper gastrointestinal mucosa, caution must hitherto be used when alendronate sodium is given to patients with active upper gastrointestinal problems, such as dysphagia, oesophageal diseases, gastritis, duodenitis, or ulcers.
The fear of adherence of the tablet to the esophagus calls for the tablet administration compulsorily with a glass of water.
Disintegration in the oesophagus or stomach causes moderate annoying side effects. The most frequently reported side effects include diarrhea or constipation, headache, stomach gas or fullness, nausea, changes in taste, and muscle pain. More serious side effects include stomach pain, heartburn, pain or difficulty swallowing, black or tarry stools, skin rash, itching (hives) and facial swelling. Signs of a possible allergic reaction are rash, swelling, and difficulty breathing.
The instructions to the patient are that he/she should sit erect or keep walking.
Specific instructions given to patient taking alendronate sodium are as follows:
1. After getting up for the day, swallow alendronate sodium tablet with a full glass 250 ml of water.
2. After swallowing alendronate sodium tablet do not lie downxe2x80x94stay upright (sitting or standing) for at least 30 minutes and until after your first food of the day. This will help the tablet reach the stomach quickly and help avoid irritation of your esophagus.
3. After swallowing the tablet, wait at least 30 minutes before taking the first food, beverage, or other medications. Alendronate sodium must be taken on a totally empty stomach.
4. Do not take alendronate sodium at bedtime or before getting up for the day.
An object of this invention is to provide a delivery vehicle for the drug where there is no fear of the tablet adhering to the walls of the esophagus and at the same time the drug is released in the stomach or in the duodenum area.
Another object of this invention is to enable the drug to be taken even by a patient with oesophageal problems.
Still another object of this invention is to permit the patient to take the drug even at the time of going to bed and independent of the food intake.
Still another object of the invention is to permit a patient to take the drug along with any normal food or drink including fruit juices.
According to this invention there is provided an oral composition in tablet form containing therapeutic amounts of alendronate sodium for release of the alendronate sodium in the stomach and by passing the oesophagus, comprising a compacted granulated core with the alendronate sodium embedded in a hydroxypropyl methyl cellulosic matrix, lined with a moisture barrier film and enclosed in a sugar based inert fiber shell.
Therefore the object of this invention is achieved by imbedding the drug in a hydrophillic hydroxy propyl methyl cellulose matrix, and forming a shell around the core tablet with a sugar in an inert fiber matrix.
In accordance with a process of this invention, there is no fear of adherence to esophagus. The drug is released directly into the stomach (the site of absorption) and the swallowing of the tablets is made much simpler and no postural restrictions are required any longer. The formulation is modified to release the drug at the site of absorption. The hydrophilic matrix and the sugar inert fiber shell used impart the above characteristics.
In accordance with the process of this invention, predetermined quantities of alendronate sodium is sifted and mixed with sifted hydroxy propyl methyl cellulose, lactose and maize starch in a planetary mixer and the mixing is done at slow speed [13 to 26 r.p.m.] for 0 to 20 minutes.
Separately a homogenous smooth paste is made with maize starch blended in purified cold water and mixed in purified hot water above 80 degrees Celsius. The smooth paste is cooled to around 55 degrees Celsius and is poured into the planetary mixture containing the alendronate sodium and the mixture is mixed at a slow speed [13 to 26 r.p.m.] to obtain uniform dough. The wet uniform dough is passed through a multimill having a 10-mesh screen to obtain granules. The granules are dried typically in a fluidized bed dryer for 60 to 120 minutes at temperature ranging between 50 to 70 degrees Celsius or in a tray drier.
The dried granules are sifted on a Vibrosifter to ensure that alendronate embedded-granules pass through 20-mesh sieve. Oversized granules are passed back to the multimill for size reduction. The sifted dried granules are lubricated in the planetary mixer by applying a lubrication coating of a stearate typically magnesium stearate.
The lubricated granules are then taken up for compression in a tablet compression machine to obtain compressed core tablets.
The compressed core tablets are transferred to a coating pan where the core tablets are coated with a multiply moisture barrier film coat, typically of shellac or combination of ethyl cellulose, shellac and ethyl cellulose etc.
The core tablets coated with the moisture barrier film coating are then taken up for sugar shell formation around the core tablets.
As a first step to core formation, a primer coat of dilute sugar solution is applied on the moisture barrier film coated core tablets. The coating is done in a coating pan and after each coat of the primer; talc is sprinkled over the tablets. After the application of primer coat, the primer coat applied tablets are dried with the help of a blower.
A sugar-based shell is formed over the primer-coated tablets in a coating pan. The shell material consists of a mixture containing filtered sugar solution, a cellulose based matrix such as of carboxy methyl cellulose, methyl cellulose, ethyl hydroxy cellulose, a glossing agent, a surfactant for decreasing surface tension and improving blending, a plasticizer such as polyethylene glycol for improving the elasticity of the matrix, a binder such as Polyvinyl pyrolidine, gelatin, gum acacia for binding the sugar molecules with the inert fiber matrix, a smoothener, a glidant and lubricant such as talc and colloidal silicon dioxide. The mixture is homogenized by stirring for at least 30 minutes at speeds ranging from 1000 to 5000 r.p.m. And the shell material is introduced in the coating pan and the material is coated on the primer coated tablets by rotating the pan, sprinkling talc and drying the tablets after each coat with a hot air blower. Typically thirty such coats of the shell material are applied on the tablets.
The sugar coatings of the shell material prevent the disintegration of the tablet until the tablet reaches the stomach linings. The moisture barrier layer also prevents any form of moisture from reaching the core tablets ensuring that the core tablet remains intact until the tablet has settled in the stomach linings.
The sugar based shell and the moisture barrier film coating ensure that there is absolute no contact between alendronate sodium and the oesophageal lining.